Use of an agent consisting of antibodies and/or insulin-like growth factor antagonists

ABSTRACT

The present invention relates to the use of a composition selected from the group consisting of antibodies, antibody fragments, insulin-like growth factor antagonists, Toll-like receptor antagonists and mixtures thereof for the treatment or the prophylaxis of certain diseases.

TECHNICAL FIELD

The present invention relates to the use of an agent selected from thegroup consisting of antibodies, antibody fragments, insulin-like growthfactor antagonists, Toll-like receptor antagonists and mixtures thereoffor the treatment or the prophylaxis of certain diseases.

Diseases of the human body are currently treated with an abundance oftherapeutic agents. Similarly, a large number of agents are employed forthe prophylaxis of diseases. In spite of this large number of treatmentoptions, there is a permanent need for novel therapy and prophylaxisagents, for the development of novel therapy methods and for theimprovement and further development of known therapy methods.

For certain diseases (e.g. chronic pain syndromes), it has hitherto beenknown from the state of the art that antibodies against endotoxins canbe employed in their treatment. Endotoxins are decomposition products ofbacteria, which can trigger numerous physiological reactions in humans.Antibodies against endotoxins are also contained in the natural antibodyspectrum of bovine colostrum.

The oral use of immunoglobulins from plasma, colostral milk, milk, eggsor cell cultures for the treatment and prophylaxis of chronic states ofpain without physiological correlation is disclosed in the state of theart (DE 195 48 221 C1).

W. G. Struff and G. Sprotte, Int. J. Clin. Pharmacol. Ther., 2007 April;45(4):193-202 disclose biotechnological standards, pharmacodynamic andpharmacokinetic characteristics and treatment methods of bovinecolostrum.

W. G. Struff and G. Sprotte, Int. J. Clin. Pharmacol. Ther., 2008 May;46(5):211-25 disclose clinical studies with bovine colostrum.

A. M. Waaga-Gasser et al., Int. J. Clin. Pharmacol. Ther., 2009 July;47(7):421-33 disclose the treatment of patients suffering from chronicpain syndrome with oral immunoglobulin from bovine colostrum.

A. Goebel et al. disclose data which show an increased permeability inthe gastroduodenal region and in the small intestine in the presence oftwo chronic pain syndromes (fibromyalgia and complex regional painsyndrome).

The object of the present invention was thus to provide agents whichpositively influence, in particular improve the prophylaxis and/ortherapy of certain diseases. The certain diseases in this context arediseases selected from group X consisting of:

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases.

A further (part) object of the present invention was to providecompositions which influence, in particular improve the treatment or theprophylaxis of a disease selected from group Y as described below, andin particular the diseases

-   -   irritable bowel syndrome    -   reactive arthritis    -   ulcerative colitis    -   Crohn's disease    -   graft-versus-host disease.

The present objects are achieved by the subject matter of theindependent claims.

SUMMARY OF THE INVENTION

A first embodiment of the present invention accordingly relates to anagent selected from the group consisting of antibodies, antibodyfragments, insulin-like growth factor antagonists, Toll-like receptorantagonists and mixtures thereof for the treatment or the prophylaxis ofa disease having anatomically pathological correlations, selected fromgroup X consisting of

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   lateral epicondylitis    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases        where in the case of asthma in the case where the agent        comprises neither an insulin-like growth factor antagonist nor a        Toll-like receptor antagonist    -   (i.) the treatment or prophylaxis is carried out orally and/or    -   (ii.) the antibodies and/or antibody fragments target        Gram-negative bacteria to the extent of at least 5 wt. %,        preferably 10 wt. %, based on the total antibody content of the        agent.

A further embodiment of the present invention relates to an agentselected from the group consisting of antibodies, antibody fragments,insulin-like growth factor antagonists, Toll-like receptor antagonistsand mixtures thereof for promotion of the apoptosis of monocytes whichhave taken up lipopolysaccharides, in the treatment or for theprophylaxis of a disease selected from groups X and Y consisting of

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   lateral epicondylitis    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases    -   irritable bowel syndrome    -   reactive arthritis    -   ulcerative colitis    -   Crohn's disease    -   graft-versus-host disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the pain level as the meanvalues of the numerical daily ratings for two study periods.

FIG. 2 is a graphical representation of quality of life parameters(physical exhaustion, concentration ability, mood, activity, sleepquality, bowel movement).

FIG. 3 is a graphical representation of the pain level of 3 painphenotypes by means of a sliding three-day average.

FIG. 4 is a graphical representation of the course of the quality oflife parameters (physical exhaustion, concentration ability, mood,activity, sleep quality, bowel movement) for a patient while receivingtrial medication, using a sliding three-day average.

FIG. 5 shows the change in intensity of 3 different classified painsymptoms (the three most acute pain phenotypes) of a patient throughself-assessment using NRS values after initial treatment with thespecific IgY preparation.

FIG. 6 illustrates the changes in intensity of 3 different classifiedpain symptoms (epicondylitis, headache and back-sciaticpain/mononeuropathy) of a patient based on self-assessment of NRS scoresover a study period and during subsequent follow-up, when the patientcontinued to take IgY at a low maintenance dose until day 141.

FIG. 7 illustrates changes in the intensity of pain attacks resultingfrom trigeminal neuralgia by means of patient self-assessment using NRSscores for a study period.

FIG. 8 shows the action/effect of the IgY preparation on 3 quality oflife parameters (sleep quality, activity and bowel movement) in apatient, who had an extreme manifestation of irritable bowel syndromewith diarrhea.

FIG. 9 shows the result of the ELISA test for three test solutions, A, Band C.

DETAILED DESCRIPTION OF THE INVENTION

In studies conducted by ourselves, it has been found, surprisingly, thatthe diseases mentioned can be influenced by a common mechanism.

The studies have furthermore shown, surprisingly, that the diseasesmentioned can be caused and prolonged at least partially by a defectivebiological barrier against bacterial toxins, in particular endotoxins.In addition to the defective mechanical barrier function of the mucousmembranes of the digestive tract (Goebel A. et al., Rheumatology, 2008),defective processing by immune cells of the toxins recognized as anantigen (Waaga-Gasser A. M. et al, International Journal of ClinicalPharmacology and Therapeutics, 2009) may furthermore also be mentionedas a further prerequisite for the development of disease symptoms of thediseases mentioned. However, the fact that these mechanisms also applyto the diseases of groups X and Y was not to be expected against thebackground of the state of the art.

Defective processing of bacterial antigens consists of “organized celldeath”, i.e. apoptosis, not being started to a sufficient extent in theimmune cells of the mucous membranes which take up the antigen (inparticular in the monocytes). Apoptosis usually leads to localneutralization of the toxins within the immune barrier of the digestivetract.

In patients with a defective mechanical and immunological barrierfunction, there is an excess of immune cells in venous blood whichcontinue to present bacterial toxins from the digestive tract comparedwith patients with an intact barrier function. These immune cells havenot entered into apoptosis after taking up the toxin—as would usually beexpected. In close correlation with this finding in the cell immunesystem, a constellation of a defective humoral immune response typicalof this disease mechanism is found in the serum or plasma of thepatient.

Surprisingly, it has now been possible to demonstrate in the studiesconducted a therapeutic and/or prophylactic effect in the use of anagent comprising antibodies, antibody fragments, insulin-like growthfactor antagonists and/or Toll-like receptor antagonists in patientssuffering from one or more of the diseases listed. In addition to anidiopathic pain syndrome, the patients in the studies predominantlysuffered from one or more of the diseases listed (co-morbidities).

The results of the clinical studies conducted with the use of an agentaccording to one embodiment of this invention show for the first timehealing actions on co-morbidities of these study patients. It hasmoreover been demonstrated for the first time, and surprisingly, thatendotoxins can play a pathogenic role not only in the triggering andmaintenance of chronic (hitherto idiopathic) pain syndromes, but also inthe typical symptoms of known diseases.

One embodiment according to the invention of the present invention is anagent selected from the group consisting of antibodies, antibodyfragments, insulin-like growth factor antagonists, Toll-like receptorantagonists and mixtures thereof for the treatment or the prophylaxis ofa disease selected from groups X consisting of

-   -   polyneuropathy, mononeuropathy (possibly without trigeminal        neuralgia), autonomic neuropathy, small fibre neuropathy, in        each case especially in autoimmune diseases, diabetes mellitus        type I and II, diabetes type A, B, C, D, E, F, G, H, polyclonal        gammopathy and/or kidney dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases        where in the case of asthma in the case where the agent        comprises neither an insulin-like growth factor antagonist nor a        Toll-like receptor antagonist    -   1. the treatment or prophylaxis is carried out orally and/or    -   2. the antibodies and/or antibody fragments target Gram-negative        bacteria to the extent of at least 5 wt. %, preferably 10 wt. %,        based on the total antibody content of the agent.

For further or all of the abovementioned indications, it may also bepreferable for the agent to be employed according to the invention tocomprise neither an insulin-like growth factor antagonist nor aToll-like receptor antagonist.

In the context of the present invention an antibody or antibody fragmentis a protein from the class of globulins having at least one specificantigen-binding site (paratope). Antibodies are formed in vivo as areaction to particular antigens.

Substances which, after introduction into the organism of humans andanimals, cause a specific immune response which manifests itself interalia in the formation of antibodies are called antigens.

An antigen can have several epitopes (antigen determinant,antigen-binding site) to which different antibodies in each case canbind. For this reason in vivo the formation of a mixture of antibodiesof different specificity (polyclonal antibodies) always occurs, even ifimmunization has been carried out with a single antigen. Conversely,antibodies of a single mono- or bispecificity are referred to asmonoclonal antibodies.

A particular antigen as a rule induces the formation of only a few,quite particular matching antibodies, which usually recognize only thisforeign substance via specific, non-covalent binding.

Antigens in the context of the present text are, in particular,microorganisms (species) or parts thereof.

In the context of this text, the indications described above are to beunderstood as meaning diseases having an anatomically pathologicalcorrelation. Anatomically pathological correlation here means that inparticular a detectable tissue damage is regarded as the cause of theparticular disease symptoms. Such a tissue damage can also be aninflammation and/or be caused by pathological metabolic states. It ispointed out that the above definition of anatomically pathologicalcorrelation expressly does not also include the physiological situationof the action mechanism found and described here, namely the presence oftoxin-loaded monocytes. This knowledge has not existed in the state ofthe art and was therefore not known as an anatomically pathologicalcorrelation.

Surprisingly, a therapeutic and/or prophylactic effect exists in the useaccording to the invention of an agent selected from the groupconsisting of antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists in patients sufferingfrom one or more of the diseases listed in group X and/or group Y.

The use according to one embodiment according to the invention showsfurther advantages: the use according to the invention has a lowerpotential for side effects than conventional therapeutic approaches, butthe use according to the invention is highly effective.

A further positive effect which is found in a use according to oneembodiment according to the invention is the improvement in the qualityof sleep and mood in patients affected. It has furthermore been foundthat antibodies can often also assist healing processes.

The reactive arthritis mentioned in group Y relates to inflammatorydiseases of individual large joints (monoarthritis) or of vertebraljoints (spondylarthritis/spondylarthropathy) following bacterialinfections of the digestive tract or of the urethra. These are“indirect” consequences of infections in which the pathogens themselvesdo not lead to inflammation of the joint, but bacterial antigens enterinto the joint affected by translocation in the bloodstream from thesite of the infection and trigger the inflammation “reactively” there.

The use according to the invention/the agent according to the inventionhas been found to be particularly patient-friendly in an oral treatmentand/or prophylaxis.

A preferred embodiment according to the invention thus relates to anagent according to the invention, preferably according to the precedingembodiment, characterized in that it is suitable for carrying out thetreatment or the prophylaxis orally.

Following oral intake, the agent used or the antibodies and/or antibodyfragments bind their specific antigens (and also toxins) on theirpassage through the digestive tract and also arrive at or in the mucousmembranes having a defective barrier function, where they impart to theimmune cells which have already taken up endotoxins there the antibody-or antigen-specific biological signal for apoptosis. Imparting of theapoptosis signal is also attributed to the insulin-like growth factorantagonists which can be employed alternatively or additionally.

Oral (enteral) therapy has various advantages over parenteraladministration forms (e.g. intravenous, intramuscular, subcutaneous): anoral administration in the context of a use according to the inventionis associated with a considerably lower potential for side effects forthe patient, since the agent used (or the antibodies and/or antibodyfragments) do not enter into the blood circulation. It is in factdigested like other (food) proteins in the course of thegastrointestinal passage, before it enters into the organism in the formof simple amino acids. Parenterally administered proteins (e.g. fromblood plasma or serum), on the other hand, are subject to the control ofthe immune system with respect to tolerance or defence. Only humanplasma or serum proteins are tolerated parenterally with an acceptablerisk of side effects. Oral use, on the other hand, is subject to thenatural tolerance of proteins in the digestive tract and also renderspossible the use of xenogeneic antibodies, which seems desirable aboveall from economic aspects. Furthermore, this oral therapeutic form isalso pleasanter and more convenient for the patient. No (e.g. venous)access is necessary for administration. Compared with other forms ofadministration, an improved compliance by the patient and associatedwith this an increased potential for onset of action is to be expected.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding preferred embodiments, ischaracterized in that the antibodies and/or antibody fragments at leastpartially target Gram-negative bacteria. This leads to a significantincrease in the action of the agent.

Gram-negative bacteria are preferably selected from the group consistingof Streptobacillus moniliformis, meningococcus, Chlamydophila,chlamydia, spirochetes, cyanobacteria, species of the Proteobacteriaphylum, in particular Enterobacteriaceae (Escherichia coli, Salmonella,Shigella, Klebsiella, Proteus, Enterobacter), Pseudomonas bacteria,Legionella bacteria, Neisseria bacteria, Rickettsia bacteria,Pasteurella multocida bacteria and species of the Bacteroidetes strain.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists are present at leastpartially in the form of monoclonal antibodies, polyclonal antibodies,primatized monoclonal antibodies, antibody fusion proteins, antibodyfragments, conjugated antibodies, radioactively labelled antibodies,bispecific antibodies and/or monoclonal intrabody antibodies.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists are present at leastpartially in the form of monoclonal antibodies, where the monoclonalantibodies are selected from the group consisting of murine, chimaeric,humanized and human monoclonal antibodies.

Very particularly preferably, in the context of the use according to theinvention the antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists are present at leastpartially in the form of human monoclonal antibodies. Human monoclonalantibodies have the lowest immunogenicity (property of triggering areaction of the immune system called an immune response) compared withmurine, chimaeric and humanized monoclonal antibodies, where murinemonoclonal antibodies cause the highest immunogenicity.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe agent comprises immunoglobulin A, immunoglobulin D, immunoglobulinE, immunoglobulin M, immunoglobulin G and/or immunoglobulin Y orconsists of these.

Very particularly preferably, in the context of a particularly preferreduse according to the invention the agent comprises immunoglobulin Y(IgY).

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists have been obtained atleast partially, but preferably completely from birds.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists have been obtained atleast partially, but preferably completely from chickens.

Agents to be used according to the invention which have been obtained atleast partially, but preferably completely from birds, in particularfrom chickens, offer the advantage inter alia of a surprisingly hightolerability when administered to humans and/or animals. In addition,these agents which are preferably to be used according to the inventioncan be prepared in a high purity (agent concentration), so that intherapeutic use the dosage quantities actually to be employed (agentplus further constituents) can be kept relatively low. As a result, theburden to the patient associated with intake of the agent is lowered.Furthermore, antibodies obtained from birds, here in particularchickens, can be prepared in an economically favourable manner, alsobecause correspondingly large animal populations exist.

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding preferred embodiments, ischaracterized in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists arepresent at least partially in the form of monoclonal antibodies,polyclonal antibodies, primatized monoclonal antibodies, antibody fusionproteins, antibody fragments, conjugated antibodies, radioactivelylabelled antibodies, bispecific antibodies and/or monoclonal intrabodyantibodies, and in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists havebeen obtained at least partially, preferably completely from chickens.

In our own studies it has been found, surprisingly, that particularlygood results were achieved when using the agent according to theinvention if the antibodies, antibody fragments, insulin-like growthfactor antagonists and/or Toll-like receptor antagonists were obtainedat least partially from chickens. A surprisingly great improvement intolerability thus existed in patients compared with agents according tothe invention which are to be used from mammals, here in particularcattle.

A particularly preferred agent according to the invention, preferablyaccording to one of the preferred preceding embodiments, ischaracterized in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists havebeen obtained at least partially from liquid and/or dried egg yolk.

A further particularly preferred agent according to the invention,preferably according to one of the preceding embodiments, ischaracterized in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists havebeen obtained at least partially from solid egg yolk powder, preferablyfrom dried defatted egg yolk powder.

Defatted egg yolk powder is obtained by standard processes (removal offat from dried egg yolk powder), preferably using hexane. After theremoval of fat, the defatted egg yolk powder is dried again.

A very particularly preferred agent according to the invention,preferably according to one of the preceding embodiments, ischaracterized in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists havebeen obtained at least partially from dried, defatted egg yolk powder,where the defatted egg yolk powder has been obtained from chicken'seggs.

In the studies we conducted ourselves, surprisingly, the extendedantibody spectrum from natural biological sources, in particular fromegg yolk, proved to be particularly active. The origin of the agents tobe used according to the invention is regularly to be detected fromco-substances accompanying the agent. Thus, the agents obtained from eggyolk typically comprise, for example, lipoproteins, such as HDL and LDL,and the water-soluble proteins of the egg yolk, α-livetin (80 kDa),β-livetin (45 kDa) and/or γ-livetin (150 kDa, which also comprise mostof the enzymes found in the egg (Ternes, Acker and Scholtyssek, Ei andEiprodukte, 1994).

A particularly preferred agent according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe agent is a medicament or a constituent of a medicament and/or aconstituent of a formulation prepared for administration.

A very particularly preferred agent according to the invention,preferably according to one of the preceding embodiments, ischaracterized in that the agent is a medicament or a constituent of amedicament and/or a constituent of a formulation prepared foradministration, where (preferably bovine) colostrum is used.

In the context of the present invention, the first milk for mammalsproduced by the female mammary gland to provide optimum nutrition forthe newborn in the first days is called bovine colostrum. It is alsocalled pre-milk, colostral milk or beastings (in cows) and comprisesproteins, enzymes, vitamins, minerals, growth factors, amino acids andantibodies.

Medicaments or equally medical preparations in the context of thisinvention are substances or substance compositions which are intended asagents having properties for healing or for prevention of human oranimal diseases or can be used in or on the human or animal body oradministered to a human or animal in order either to re-establish, tocorrect or to influence the human or animal physiological functions by apharmacological, immunological or metabolic action or to establish amedical diagnosis. Preferably, in the context of this text “medicament”is to be understood as meaning a corresponding substance and/or acorresponding substance mixture for which approval exists according tothe medical preparations law of the particular country of use,particularly preferably approval according to German medicalpreparations law. The preferred medicaments in the context of thisapplication text also include so-called “orphan medicaments” (orphandrugs) which are subject to a simplified approval procedure andpreferably are approved according to European and/or US law.

A preferred agent according to the invention, preferably according toone of the preceding embodiments, is characterized in that the agent isa constituent of a formulation prepared for administration, where theformulation prepared is selected from the group consisting ofpharmaceutical preparations, cosmetic preparations, foodstuffs, foodsupplements, functional food and medicinal products, and feedstuffs,feed supplements and dietary feed supplements for use in animals.

According to the invention, foodstuffs and corresponding newly developedproducts to which more than only the pure nutritional and flavour valueare added on the basis of particular constituents are summarized as“functional food”. Synonymously, but partially also as differentiation,the terms nutriceuticals, foodsceuticals and designer foods are used,which likewise represent embodiments of the preparation in the contextof the invention.

In our own studies it has been found, surprisingly, that particularlygood results are obtained by a use according to the invention,preferably according to one of the preceding embodiments, where theagent is a constituent of a formulation prepared for administration, ifthe agent contained in the formulation prepared has been obtained atleast partially from chickens, preferably from the egg yolk of chickens.

The antibody-containing protein content of egg yolk can be pasteurized,so that the concentration of pathogenic germs can be adequately loweredwithout a substantial loss of antibody activity in the product. Thisstarting product for the preparation of a formulation (a preparation tobe used according to the invention) prepared for administration can bedistinguished from the foodstuff egg yolk by analysis of the antibodyspectrum, for example by ELISA or neutrality tests.

Such starting products (antibodies from egg products) are conventionallysubjected to conventional concentration processes, such as e.g. theusual defatting processes by means of various solvents, such as hexane,ethanol, acetone or carbon dioxide or further processes by means of:

-   -   hydroxypropylmethylcellulose (Yokoyama H. et al., A 2-step        procedure for purification of chicken egg-yolk        immunoglobulin-G-utilization of hydroxypropylmethylcellulose        phthalate and synthetic affinity ligand gel, 1993, Poultry        Science, 72, pp. 275-281.)    -   polyethylene glycol, dextran sulfate, xanthan (Akita E. M.,        Nakai S., Comparison of four purification methods for the        production of immunoglobulins from eggs laid by chickens        immunized with an enterotoxogenic E. coli strain, 1993, Journal        of Immunological Methods, 160 (2), pp. 207-214.)    -   ethanol (Toshio Horikoshi, et al., IgG Antibody from Hen Egg        Yolks: Purification by Ethanol, 1993, Fractionation Journal of        Food Science 58 (4), 739-742.)    -   ultrafiltration (Hernandez-Campos F J et al., Purification of        Egg Yolk Immunoglobulin (IgY) by Ultrafiltration: Effect of pH,        Ionic Strength, and Membrane Properties, Journal of Agricultural        and Food Chemistry, 2009 Dec. 8. [Epub ahead of print])    -   lithium sulfate (Bizhanov G. et al., A novel method, based on        lithium sulfate precipitation for purification of chicken egg        yolk immunoglobulin Y, applied to immunospecific antibodies        against Sendai virus, 2004, Scandinavian Journal of Laboratory        Animal Science, 31 (3), pp. 121-130.).

The mixture consequently comprises further co-factors, in addition tothe agent to be used according to the invention, which are the basis forthe preparation to be used according to the invention. These co-factorscan have a positive effect on the action mechanism and/or thetolerability of the preparation to be used according to the invention.

A preferred use according to the invention of the agent according to theinvention, preferably according to one of the preceding embodiments, ischaracterized in that the treatment or the prophylaxis is carried out bya daily dose of a formulation prepared for administration of 0.1-10.0 g,preferably 1.0-8.0 g, further preferably of 2.0-7.0 g.

A very particularly preferred use according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe treatment or the prophylaxis is carried out by a daily dose of aformulation prepared for administration of 0.1-10.0 g, preferably1.0-8.0 g, further preferably of 2.0-7.0 g, where at least 1.5 wt. %,preferably at least 2.0 wt. %, further preferably at least 5.0 wt. % ofthe formulation prepared for administration is antibodies and/orantibody fragments, based on the total weight of the formulation.

In the case where a formulation of higher concentration with respect toits antibody content is used, it goes without saying for the personskilled in the art to adapt the dosage of the corresponding formulationprepared for administration. In this case, preferred daily doses are 0.1g-5 g, further preferably 0.1 g-2 g. A higher activity of a formulationcan also be achieved by the use of enteric coatings and/orencapsulations. A combination in which a more highly concentratedformulation is used with an enteric coating and/or encapsulation islikewise possible.

A very particularly preferred use according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe treatment or the prophylaxis is carried out by a daily dose of aformulation prepared for administration having an enteric coating and/orhaving an enteric encapsulation of 0.1-5 g, preferably 0.1-2 g.

A enteric coating or an enteric encapsulation offers the advantage thatantibodies contained in the formulation prepared for administration arenot denatured during passage through the stomach.

A still further preferred use according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe treatment or the prophylaxis is carried out by a daily dose of aformulation prepared for administration of 0.1-10.0 g, preferably1.0-8.0 g, further preferably of 2.0-7.0 g, where at least 1.5 wt. %,preferably at least 2.0 wt. %, further preferably at least 5.0 wt. % ofthe formulation prepared for administration is antibodies and/orantibody fragments, based on the total weight of the formulation, andwhere still preferably the content of IgY antibodies and/or IgY antibodyfragments is at least 30%, preferably 60%, further preferably 90% andparticularly preferably 100%, based on the total antibody content of theformulation prepared for administration.

A preferred use according to the invention, preferably according to oneof the preceding preferred embodiments, is characterized in that thetreatment or the prophylaxis is carried out by a daily administrationfor 4-14 weeks, preferably for 8-12 weeks. A 12-week therapy isparticularly preferred. For the above dosage information and durationsof therapy, particularly good therapeutic effects with a simultaneouslysurprisingly good tolerability have been found for a large number ofpatients.

A preferred use according to the invention, preferably according to oneof the preceding preferred embodiments, is characterized in that thetreatment or the prophylaxis is carried out by a long-term therapy.

A further embodiment according to the invention of the present inventionis

-   -   a) an agent selected from the group consisting of antibodies,        antibody fragments, insulin-like growth factor antagonists,        Toll-like receptor antagonists and mixtures thereof, or    -   b) a preparation which comprises an agent selected from the        group consisting of antibodies, antibody fragments, insulin-like        growth factor antagonists, Toll-like receptor antagonists,        for the preparation of a medicament for the treatment or the        prophylaxis of a disease selected from group X,        where in the case of asthma in the case where the agent        comprises neither an insulin-like growth factor antagonist nor a        Toll-like receptor antagonist    -   1. the treatment or prophylaxis is carried out orally and/or    -   2. the antibodies and/or antibody fragments target Gram-negative        bacteria to the extent of at least 5 wt. %, preferably 10 wt. %,        based on the total antibody content of the agent.

A further embodiment according to the invention of the present inventionis an agent selected from the group consisting of antibodies, antibodyfragments, insulin-like growth factor antagonists, Toll-like receptorantagonists for promotion of the apoptosis of monocytes which have takenup lipopolysaccharides, in the treatment or for the prophylaxis of adisease selected from groups X and Y consisting of

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases    -   irritable bowel syndrome    -   reactive arthritis    -   ulcerative colitis    -   Crohn's disease    -   graft-versus-host disease.

A particularly preferred formulation prepared for administration for theuses according to the invention is an antibody product comprising nspecific antibodies

characterized in that

-   -   a) the n specific antibodies each have an antibody content of at        least 6/n wt. %, based on the total antibody content of the        antibody product, and    -   b) 2, 3 or more of the n specific antibodies target        lipopolysaccharide-expressing microorganisms and    -   c) the total content of the n specific antibodies is 7 wt. %,        based on the total antibody content of the antibody product.

Lipopolysaccharides are compounds of fat-like (lipo-) constituents andsugar constituents (polysaccharides). They are contained e.g. in theouter membrane of Gram-negative bacteria and act as antigens. Duringdecomposition of the bacteria, parts of the lipopolysaccharides becomefree and have a toxic action. These parts are called endotoxins.

Precise information on particularly preferred formulations prepared foradministration are to be found in the German patent application with theofficial application number DE 10 2011 006 781.7, where still furtherpreferred embodiments are also described.

In contrast to agents available to date, which comprise antibodiesagainst endotoxins (e.g. bovine colostrum), such a particularlypreferred formulation prepared for administration has a bettertolerability.

The invention likewise discloses agents A selected from the groupconsisting of antibodies, antibody fragments, insulin-like growth factorantagonists, Toll-like receptor antagonists and mixtures thereof for usein the treatment or for the prophylaxis of a disease having ananatomically pathological correlation, selected from the groupconsisting of

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases        where in the case of asthma in the case where the agent A        comprises neither an insulin-like growth factor antagonist nor a        Toll-like receptor antagonist    -   1. the treatment or prophylaxis is carried out orally and/or    -   2. the antibodies and/or antibody fragments target Gram-negative        bacteria to the extent of at least 5 wt. %, preferably 10 wt. %,        based on the total antibody content of the agent.

A particularly preferred agent A according to the invention, preferablyaccording to the preceding embodiment, is characterized in that thetreatment or the prophylaxis is carried out orally.

A further preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies and/or antibody fragments at least partially targetGram-negative bacteria.

A similarly preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists are present at leastpartially in the form of monoclonal antibodies, polyclonal antibodies,primatized monoclonal antibodies, antibody fusion proteins, antibodyfragments, conjugated antibodies, radioactively labelled antibodies,bispecific antibodies and/or monoclonal intrabody antibodies.

A preferred agent A according to the invention according to thepreceding embodiment is characterized in that the monoclonal antibodiesare selected from the group consisting of murine, chimaeric, humanizedand human monoclonal antibodies.

A further preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe agent comprises immunoglobulin A, immunoglobulin D, immunoglobulinE, immunoglobulin M, immunoglobulin G and/or immunoglobulin Y.

A further preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists have been obtained atleast partially, but preferably completely from birds.

A further preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists have been obtained atleast partially, but preferably completely from chickens.

A similarly preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe antibodies, antibody fragments, insulin-like growth factorantagonists and/or Toll-like receptor antagonists have been obtained atleast partially, but preferably completely from liquid and/or dried eggyolk.

A very particularly preferred agent A according to the invention,preferably according to one of the preceding embodiments, ischaracterized in that the antibodies, antibody fragments, insulin-likegrowth factor antagonists and/or Toll-like receptor antagonists havebeen obtained at least partially from solid egg yolk powder, preferablyfrom dried defatted egg yolk powder.

A still further preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe agent is a medicament or a constituent of a medicament and/or aconstituent of a formulation prepared for administration.

A preferred agent A according to the invention, preferably according toone of the preceding embodiments, is characterized in that the treatmentor the prophylaxis is carried out by a daily dose of a formulationprepared for administration of 0.1-10.0 g, preferably 1.0-8.0 g, furtherpreferably of 2.0-7.0 g.

A very particularly preferred agent A according to the invention,preferably according to one of the preceding embodiments, ischaracterized in that the treatment or the prophylaxis is carried out bya daily dose of a formulation prepared for administration of 0.1-10.0 g,preferably 1.0-8.0 g, further preferably of 2.0-7.0 g, where at least1.5%, preferably at least 2.0%, further preferably at least 5.0% of theformulation prepared for administration is antibodies and/or antibodyfragments, based on the total weight of the formulation.

An extremely preferred agent A according to the invention, preferablyaccording to one of the preceding embodiments, is characterized in thatthe treatment or the prophylaxis is carried out by a daily dose of aformulation prepared for administration of 0.1-10.0 g, preferably1.0-8.0 g, further preferably of 2.0-7.0 g, where at least 1.5%,preferably at least 2.0%, further preferably at least 5.0% of theformulation prepared for administration is antibodies and/or antibodyfragments, based on the total weight of the formulation, and where thecontent of IgY antibodies and/or IgY antibody fragments is at least 7%,based on the total antibody content of the formulation prepared foradministration.

A preferred agent A according to the invention, preferably according toone of the preceding embodiments, is characterized in that the treatmentor the prophylaxis is carried out by a daily administration for at least4 weeks, preferably for at least 8 weeks, particularly preferably for atleast 12 weeks.

A preferred agent A according to the invention, preferably according toone of the preceding embodiments, is characterized in that the treatmentor the prophylaxis is carried out by a long-term therapy.

The invention likewise discloses

-   -   a) agents A selected from the group consisting of antibodies,        antibody fragments, insulin-like growth factor antagonists,        Toll-like receptor antagonists and mixtures thereof, or    -   b) preparations which comprise an agent A selected from the        group consisting of antibodies, antibody fragments, insulin-like        growth factor antagonists, Toll-like receptor antagonists,        for the preparation of a medicament for the treatment or the        prophylaxis of a disease selected from group X,        where in the case of asthma in the case where the agent A        comprises neither an insulin-like growth factor antagonist nor a        Toll-like receptor antagonist    -   1. the treatment or prophylaxis is carried out orally and/or    -   2. the antibodies and/or antibody fragments target Gram-negative        bacteria to the extent of at least 5 wt. %, preferably 10 wt. %,        based on the total antibody content of the agent.

All the advantages and embodiments disclosed with respect to the usesaccording to the invention are applied mutatis mutandis to the agents Aaccording to the invention or formulations for use in the treatment orfor the prophylaxis of a disease selected from group X.

The invention likewise discloses agents A selected from the groupconsisting of antibodies, antibody fragments, insulin-like growth factorantagonists, Toll-like receptor antagonists and mixtures thereof forpromotion of the apoptosis of monocytes which have taken uplipopolysaccharides, for use in the treatment or for the prophylaxis ofa disease selected from groups X and Y consisting of

-   -   polyneuropathy, mononeuropathy, autonomic neuropathy, small        fibre neuropathy, in each case especially in autoimmune        diseases, diabetes mellitus type I and II, diabetes type A, B,        C, D, E, F, G, H, polyclonal gammopathy and/or kidney        dysfunctions    -   peripheral nerve compression syndromes (such as carpal tunnel        syndrome), ulnar nerve entrapment syndrome (cubital tunnel        syndrome, Morton's metatarsalgia, Bernhardt-Roth syndrome        (meralgia paraesthetica), thoracic outlet syndrome (TOS))    -   arthrosis other than osteoarthrosis; in particular activated        arthrosis, primary arthrosis, secondary arthrosis    -   enthesiopathies in collagenoses    -   lateral epicondylitis    -   achillodynia    -   calcaneodynia and heel spur    -   periarthritis humero-scapularis    -   Tietze's syndrome (sternoclavicular joint arthropathy)    -   arthropathy of the iliosacral joint    -   myoarthropathy of the masticatory apparatus, craniomandibular        dysfunction    -   cervical spine syndrome after deceleration trauma    -   diverticulitis in colonic diverticulosis    -   neurodermatitis    -   asthma    -   interstitial cystitis (painful bladder syndrome)    -   food allergy    -   allergy to light, in particular polymorphic photodermatosis    -   mucositis, in particular oral mucositis and/or mucositis after        radiation therapy (radiogenic mucositis) and/or mucositis after        and/or under chemotherapy    -   mucosal ulcers in Behcet's syndrome    -   mucosal erosions in pemphigus vulgaris    -   mucosal lesions in scleroderma    -   mucosal lesions in Sjörgen's syndrome    -   migraine without aura    -   cardiovascular diseases    -   irritable bowel syndrome    -   reactive arthritis    -   ulcerative colitis    -   Crohn's disease    -   graft-versus-host disease.

All the advantages and embodiments disclosed with respect to the usesaccording to the invention are applied mutatis mutandis to the agents Aaccording to the invention for use in the treatment or for theprophylaxis of a disease selected from group Y.

The present invention is illustrated in more detail in the followingwith the aid of examples, where the invention is not limited to thefollowing examples.

Unless stated otherwise, all the (amounts) data here relate to theweight.

EXAMPLES Preparation Example 1

Precise information on the preparation of the preparation example are tobe found in the German patent application having the officialapplication number DE 10 2011 006 781.7 or in PCT/EP2012/055456 (bothincluded via reference). The preparation obtained in accordance with theinformation there (dried, defatted egg yolk powder) was employed in thefollowing examples. The preparation comprised specific antibodiesagainst the following antigens:

-   -   CA-GTase from Streptococcus mutans serotype c from the cells of        MT8148    -   gingipain from the membrane of Poryphyromonas gingivalis (ATCC        33277)    -   Candida albicans cells (JCM 1542)    -   Escherichia coli F18 cells, serotype F107 (107/86)    -   alpha- and beta-toxin from Clostridium perfringens type C        (NCTC3227)    -   antigen according to H. Yokoyama et al. of the Salmonella        typhimurium cell (ATCC-13311).

The preparation comprised a total antibody content of approx. 2 wt. %,based on the total weight of the preparation. The total antibody contentcomprised approx. 10 wt. % of specific antibodies against the antigentypes employed (listed above), based on the total antibody content ofthe preparation. Each specific antibody type (targeting one of the aboveantigen types employed) was present in the preparation with a content ofapprox. 10/6 wt. %, based on the total antibody content of thepreparation.

Preparation Example 2

Preparation Example 2 was prepared analogously to Preparation Example 1,but the following antigens

-   -   Escherichia coli F18 cells, serotype F107 (107/86),    -   alpha- and beta-toxin from Clostridium perfringens type C        (NCTC3227),    -   antigen according to H. Yokoyama et al. of the Salmonella        typhimurium cell (ATCC-13311)        were employed for the immunization.

Preparation Example 2 was moreover used in formulations such aseffervescent powders and tablets (in particular enteric tablets). Theamount of Preparation Example 2 employed is 0.375 g per tablet or 5 gper pack unit of effervescent powder.

It should be emphasized once more at this point that for the use and theactivity of the products according to the invention, the decisive factoris the content of specific antibodies (polyclonal or monoclonal). Sincethe preparation employed for the following examples is a product whichhas been obtained from natural sources (eggs from chickens), certainvariations in the constituents are of course usual and unavoidable.

Action Example

Neutralization Capacity of the IgY Preparation (Preparation Example 2)

Blood was taken from a healthy volunteer and was then treated withheparin such that it no longer coagulates. Heparin blood results. Theheparin blood was then separated into its constituents in order toobtain the blood plasma. 2 ml of the blood plasma obtained in this waywere incubated with 2 ml of E. coli control standard endotoxin (50EU/ml) at 37° C. and 5% CO₂ for 24 hours. A base plasma solution whichcomprises a defined amount of a standardized endotoxin is formed.Further notes on the standard endotoxin used can be found in thedescription of Limulus Amoebocyte Lysate, Endosafe Endochrome-K TestSystem (US Licence no. 1197).

Provision of the Test Solutions:

Test solution B: test solution according to the invention against E.coli, Salmonella and C. perfringens (Preparation Example 2)

In a step a) 100 μl of the base plasma solution prepared were removedand were then mixed homogeneously in a step b) with 100 μl of thedissolved test substance (IgY; 0.25 g/ml, from Preparation Example 2dissolved in water). The dissolved test substance comprised a mixture ofantibodies according to the invention against E. coli, Salmonella and C.perfringens (Preparation Example 2). In a subsequent step c) thesolution prepared in this way was incubated at 37° C. and 5% CO₂ for afurther 3 hours. In a subsequent step d) the solution was diluted to anendotoxin concentration of 2 EU/ml by addition of water, taking intoaccount the later addition of the LAL reagent, and in a step e) wasincubated at 75° C. in a water bath for 5 minutes (inactivation).

The test solution inactivated in this way was then investigated with theaid of the LAL test (Endosafe Endochrome-K Test System). For this, theinactivated test solution was mixed with the LAL reagent, taking intoaccount the method provided by the manufacturer, and the mixture wasthen pipetted on to a 96-well plate. The investigation was carried outby an ELISA reader and a subsequent evaluation.

Test Solution A: Comparison Solution (Control Solution) which ComprisesNo Antibodies

Test solution A was prepared analogously to test solution B, with thedeviation that under step a) 200 μl of base plasma solution were removedand step b) was not carried out.

Test Solution C: Comparison Solution Comprising Antibodies not Accordingto the Invention (IgG, Lactobin N; Dr. Wolz Zell GmbH)

Test solution C was prepared analogously to test solution B, with thedeviation that under step b) 100 μl of a Lactobin N solution(manufacturer: Dr. Wolz Zell GmbH) were used. The antibody concentrationcorresponded to the concentration in test solution B.

FIG. 9 (FIG. 9) shows the result of the ELISA test for test solutions A,B and C. The test quantifies the amount of free endotoxin in theparticular test solutions.

Test solution A (control solution), which comprises no antibodies forneutralization of the endotoxins, shows the highest amount of freeendotoxin.

Test solution B according to the invention, in contrast, shows thelowest amount.

Compared with test solution C (comparison solution with Lactobin N),test solution B according to the invention shows a significantly betterneutralization of the endotoxin than when Lactobin N is used.

USE EXAMPLES Example 1

Patient data: 32 years old, female

Duration of the pain syndrome: 9 years

Diagnosis:

Complex regional pain syndrome (CRPS type II) after complex injury ofthe right thumb with fractures of the proximal and distal phalanges anddamage to the nerve supply.

After 3 surgical interventions (osteosynthesis of the fracture, removalof metal, surgical correction of deformed extensor tendons) persistentpain at rest and increased during and above all after exercise (painfulpost-traumatic mononeuropathy).

Local Findings:

Burning stabbing sensations in the whole of the thumb area, more acuteat the site of the scars, here also with spontaneous shooting pain andpain triggered by gentle touch (allodynia), and referred pain whenpressure applied (Hoffmann-Tinel sign on the damaged skin nerve). Inaddition, constant throbbing and stinging pain (deep pain) in the twoproximal joints of the thumb. Radiographic evidence of arthrosis (painconsistent with activated arthrosis) in these two joints. Compared tothe left thumb, the right thumb is significantly narrower, i.e. the skinand soft tissue of the thumb are thinner (atrophy).

Therapeutic Response of the Pain:

No alleviation of pain by centrally and peripherally acting analgesics,antidepressants, anticonvulsives, transcutaneous electrical nervestimulation.

Opiate injections in the cervical sympathetic trunk of the sympatheticnervous system (GLOA) completely eliminates all pain for an average of48 hours.

Evidence of a Considerable Improvement in the Disease Symptoms with OralTherapy with a Hyperimmunoglobulin Against Endotoxin (LPS) from Egg Yolkof Immunized Chickens (Anti-LPS Hyper-IgY):

The patient was included in a therapy study with anti-LPS hyper-IgY.Study period of 4 weeks, divided into two equal time sections of 14 dayswith a different dosage of the study preparation, testing of theclinical effect (journal documentation of the pain and the parameters ofthe quality of life) and the effects on a broad spectrum ofimmunological laboratory parameters before the start and at the end ofthe study medication.

Therapeutic Effect:

In the first two weeks of the study, daily intake of 2×1.25 g of thepreparation (daily dose 2.5 g), including continued elimination of thedeep throbbing, pounding pain in the structures near the joint of theright thumb (arthritic pain); neuropathic surface pain in the scarregion was unchanged at this dose.

In the second study period, also over a period of two weeks, dailyintake of 2×2.5 g of the preparation (daily dose 5 g), resulting also insubstantial improvement in neuropathic pain components (see FIG. 1).With the start of freedom from pain and significant recovery in mosthand functions, there was also an improvement in concentration ability,range of activity (activity), symptomatic daytime fatigue (chronicfatigue syndrome, physical exhaustion), sleep quality and mood (see FIG.2).

In the laboratory part of the study, there was a significant reductionof endotoxin-activated monocytes in the peripheral blood (reductionthrough apoptosis), a decrease in the total number of monocytes tonormal values, and quantitative analysis of 22 immuno-messengers(chemokines, cytokines, growth factors) showed a variable but inprinciple consistent reduction in the plasma concentrations ofinflammatory proteins and a significant increase in mostanti-inflammatory protein factors.

Withdrawal Attempts:

After completion of the study the trial medication was continued due toa lack of alternatives. Treatment with IgY medication was withdrawntwice, with pain and general symptoms returning after 4-5 days.

Summary:

Neuropathic pain in the injured peripheral nerve region has previouslybeen presented as independent diagnoses of known aetiology andpathogenesis and these characteristics differentiated such pains fromidiopathic pain syndromes. Some medicaments are approved for thetreatment of painful mono- and polyneuropathies, and there areevidence-based treatment recommendations that include non-medicamentouselements. However, a gross mismatch between the quality of therapeuticeffects and the extent of side effects and complications points tosignificant gaps affecting both patient care and the scientific basis.

The surprisingly positive effect of the specific IgY preparation in thisfemale patient indicates that blood cell-borne endotoxins can, inindividual cases, play a causal role in the chronification of pain, evenin an injury-induced mononeuropathy.

FIG. 1 is a graphical representation of the pain level as the meanvalues of the numerical daily ratings for the two study periods.

The ordinate shows the numerical rating scale (NRS). The ordinate has avalue ranging from 0 to 10, where “0” means no pain and “10” means themaximum pain imaginable. The abscissa gives the time in days.

Along with the visual analogue scale (VAS), NRS is the most commonmethod of measuring acute and chronic pain so that meaningfulconclusions about therapeutic effects can be made based on pain diaries.Patients with chronic pain are familiar with this method of assessingthe intensity of their pain.

This patient began keeping the diary records on starting the trialmedication on day 15.

Instead of daily values, the mean values over both periods are shown.

FIG. 2 is a graphical representation of quality of life parameters(physical exhaustion, concentration ability, mood, activity, sleepquality, bowel movement).

The positive effects on quality of life parameters are shownparticularly clearly by the reduced daytime fatigue and increased rangeof activity (activity). The numerical rating scale, where 0=no diseasesymptoms and 10=maximum disease symptoms, is used here analogously tothe assessment of pain. Patients with chronic pain are familiar withthis form of assessing the severity of their symptoms by keeping a paindiary.

Example 2

Patient data: 39 years old, female

Duration of the complex pain syndrome: Soft tissue rheumatism 30 years,arthrosis 20 years, neuropathy following nerve injury 5 years

Diagnoses:

1. Soft-tissue rheumatism

2. Severe arthrosis with pain in the right knee joint on resting andexercising. Condition after joint replacements in both hips (arthrosis).

3. Painful mononeuropathy of the left sural nerve with spasticity afterirreversible nerve damage.

Local Findings:

Significant swelling and hyperthermia of the right knee joint withintolerable nocturnal resting pain, despite cooling with ice packs andintake of anti-inflammatories.

Right spastic equinus with pasty swelling, here superficial burningsensation and shooting neuralgia. Tender musculature that fatigueseasily, tenderness in tendon attachments and soft tissues of mostjoints.

Therapeutic Response of the Pain:

Despite long-term medication with antidepressants, anticonvulsives andantirheumatics, and the use of walking aids, the most important dailyfunctions were severely restricted, mainly by pain.

Evidence of a Significant Improvement in the Disease Symptoms with OralTherapy with a Hyperimmunoglobulin Against Endotoxins (LPS) from EggYolk from Immunized Chickens (Anti-LPS Hyper-IgY):

Participation in the same study as the patient in Example 1.

After 6 days of IgY treatment with the initial dose of 2×1.25 g,soft-tissue rheumatism was already alleviated and there was animprovement in some of the general quality of life parameters (see FIG.4). In the last 5 days of the study, a double daily dose (5.0 g intotal) again brought about a significant improvement in all painsymptoms, which unexpectedly was also clearly apparent in the neuralgiaof the left foot and the resting pain in the right knee joint. There wasalso a decrease in swelling and hyperthermia here, even whenanti-inflammatories were not taken (see FIG. 3).

In the laboratory part of the study, there was a significant reductionof endotoxin-activated monocytes in the peripheral blood (reductionthrough apoptosis), a decrease in the total number of monocytes tonormal values, and quantitative analysis of 22 immuno-messengers(chemokines, cytokines, growth factors) showed a consistent reduction inthe plasma concentrations of inflammatory proteins and a significantincrease in anti-inflammatory central protein factors.

Withdrawal Attempts:

Treatment with the study preparation was continued, as the positiveresults could not be achieved by any known alternative means. Efficacywas controlled and confirmed by 2 withdrawal attempts carried out in thecourse of one year.

Summary:

Oral IgY medication was surprisingly effective on neuropathic painsassociated with a mononeuropathy following peripheral nerve damage.

Moreover, in this case the pain, swelling and clinical inflammationsigns of activated arthrosis in the knee joint improved subjectively andobjectively.

Activated arthrosis is an independent diagnosis with objectiveradiological and clinical diagnostic criteria, as well as a very clearaetiology and pathogenesis.

The present example provides individual evidence that the endotoxin loadof immune cells circulating in the peripheral blood is significantlyreduced by orally administered antibodies, and that there is also acausal relationship between the endotoxin load of the blood cells andthe inflammatory activation of arthrosis in the knee joint.

For endotoxins at least, such a causal relationship has never beeninvestigated and therefore has also never been proven and is thereforeunexpected.

FIG. 3 is a graphical representation of the pain level of 3 painphenotypes by means of a sliding three-day average. The pain level isdetermined by the patient in a diary using the NRS method. Eachmeasurement point is the mean value for the 3 preceding days (“slidingthree-day average”).

FIG. 3 shows that treatment with an anti-LPS hyper-IgY triggers asynchronous reaction

-   -   of soft-tissue rheumatic pain (muscle, limb and tendon pain)    -   of pain in activated gonarthosis on the left (joint pain; mainly        arthrosis of left knee)    -   of neuropathic pain after peripheral nerve damage (right nervus        peroneus; neuralgia (peroneal lesion))

FIG. 4 is a graphical representation of the course of the quality oflife parameters (physical exhaustion, concentration ability, mood,activity, sleep quality, bowel movement) for the patient while receivingthe trial medication, using a sliding three-day average.

FIG. 4 shows that treatment with an anti-LPS hyper-IgY results in asynchronous improvement in

-   -   daytime fatigue (physical exhaustion)    -   concentration ability    -   range of activity (activity)    -   mental health (mood).

The severity of disease symptoms is represented by NRS on the ordinate.The measurement points on the ordinate are the mean values of NRS valuesfrom the patient diary for the preceding 3 days.

Example 3

Patient data: 56 years old, female

Duration of the complex pain syndrome: 13 years

Diagnoses:

1. Complex regional pain syndrome in both upper extremities

2. Bilateral meralgia paraesthetica=compression syndrome in skin nerveson the outer thigh where the nerves pass under the inguinal ligament.

3. Morton's metatarsalgia in both feet (compression syndrome in thenerves of the sole of the foot between the first and second toes)

4. Irritable bowel syndrome with severe bursts of abdominal pain (colic)predominantly localized in the lower abdomen

5. Painful bladder syndrome/interstitial cystitis (PBS/IC), a bladderdisease of unknown aetiology. There is persistent pain in the bladderwith a strong urge to urinate even when the organ contains very littleurine. It can also be very painful to urinate. There is no evidence ofany urinary tract infection or other localized pathology. Endoscopicexamination of the bladder mucosa reveals signs of inflammation. Thebiopsy usually shows an increase in eosinophil granulocyte and mastocyteinflammatory cells, which suggests an allergic inflammation.6. NeurodermatitisHistory and Local Findings:

Following a minor accident, the patient developed a complex regionalpain syndrome (CPRS) in the left hand, which spread to the whole of theupper left extremity (shoulder-arm-hand syndrome). This is a combinationof the 3 individual diagnoses: periarthropathy of the shoulder joint,epicondylitis humeri radialis, and CRPS of the hand. The patient alsohad nerve compression syndrome in the bony groove of the ulnar nerve atthe elbow with loss of sensory and motor nerve function in the affectedhand.

As the disease progressed, the patient also developed compressionsyndrome in the right metacarpal nerve (carpal tunnel syndrome).Following surgical treatment for this, a complex regional pain syndromealso then developed in the right hand so that in addition to the pain,the patient suffered a complete loss of function of both hands.

Therapeutic Response of the Pain:

While undergoing an unsuccessful daily interdisciplinary pain treatmentover the course of 6 months, the patient developed a further compressionsyndrome of the peripheral nerves in both thighs and feet (meralgiaparaesthetica and Morton's metatarsalgia).

The full clinical picture, including neurodermatitis, was eventuallytreated successfully with intravenous administration of the human C1esterase inhibitor (C1-INH) Berinert® in combination with low-molecularweight heparin. As the patient did not have a C1-INH deficiency, thiswas an off-label medication (a treatment outside of approvedindications). The treatment had to be continued at intervals of anaverage of 8 weeks.

Evidence of an Equivalent Elimination of the Disease Symptoms with OralTherapy with a Hyperimmunoglobulin Against Endotoxins (LPS) from EggYolk of Immunized Chickens (Anti-LPS Hyper-IgY):

The patient was only accepted into the IgY therapeutic study alreadydescribed in Examples 1 and 2 once the effect of the last Berinert®injections had subsided and all of the above disease symptoms, as wellas the neurodermatitis and severe headaches, had returned.

Therapeutic Effect:

Within the first week of the study, the initial dose of 2×1.25 g of IgYhad completely eliminated headaches and abdominal colic pain. At thebeginning of the second study phase (beginning of the third week oftreatment with IgY), the neuropathic pain and sensory disturbancescaused by nerve compression symptoms in both the lower and upperextremities and shoulder pain and restricted movement had alsodisappeared (see FIG. 5). The general disease symptoms of the complexhealth problem and the neurodermatitis disappeared along with the pain,although the daytime fatigue persisted at a low level to the end of thestudy period. On continuing treatment at the low initial dose, thesymptoms of fatigue then also disappeared completely in the followingmonths.

In the laboratory part of the study, there was a significant reductionof endotoxin-activated monocytes in the peripheral blood (reductionthrough apoptosis), a decrease in the total number of monocytes tonormal values, and quantitative analysis of 22 immuno-messengers(chemokines, cytokines, growth factors) revealed significant andsuccessful changes brought about by the treatment, as with all studyparticipants. In this patient, however, the greatest changes were in adifferent spectrum of chemokines.

Withdrawal Attempts:

Following the study, the study medication was continued at the lowerdose over 4 months. Symptoms only returned when the study medication wasstopped for a further 3 months.

Summary:

A surprising effect on neuropathic pain occurred, the neuropathicfunctional disturbances being caused not by injuries to the peripheralnerves but by an almost generalized compression syndrome of theperipheral nerves. This effect occurred within one week at the lowestdose and was equivalent to treatment with Berinert® in terms of quality.

The pain and dysfunction in the shoulder and elbow joint caused by anunusually acute periarthritis and epicondylitis were completelyeliminated after 15-16 days. This very common form of inflammatoryperiarticular disease was indeed associated with the mysterious systemicdisease of the patient, but the surprisingly extremely successfulresponse to IgY therapy suggests that the general nature of this diseaseis a form of the endotoxin-mediated diseases of the locomotor system. Itis therefore likely that therapy with antibody preparations,particularly the specific IgY preparation employed, may be promisingwhen used on an as yet unknown proportion of patients with thesediseases.

By this analogy, the same can be assumed for irritable bowel symptomsand symptoms of interstitial cystitis.

Even the patient's pronounced neurodermatitis did not return while shewas receiving IgY therapy. Irritable bowel syndrome, interstitialcystitis and neurodermatitis have a common immunological feature:pathologically activated mast cells are involved in proven inflammatoryorgan changes. This cell type of the immune system also has bindingsites for endotoxins, so that in particular circumstances these cellscan also be activated simultaneously in various organ systems by thesetoxins. In specific oral antibody therapy with IgY, endotoxins alreadyare partially eliminated in the intestine.

FIG. 5 shows the change in intensity of 3 different classified painsymptoms (the three most acute pain phenotypes) of this patient throughself-assessment using NRS values after initial treatment with thespecific IgY preparation. The measurement points on the ordinate are themean values of NRS ratings from the patient diary for the preceding 3days. The abscissa gives the time in days. The patient began taking IgYon day 15 and the dose was doubled from day 29.

Example 4

Patient data: 55 years old, female

Duration of the complex pain syndrome: 12 years

Diagnoses:

-   -   1. Post-zoster neuralgia of the 1st and 3rd right trigeminal        branch (trigeminal mononeuropathy after herpes zoster)    -   2. Migraine without aura    -   3. Bilateral achillodynia (inflammatory enthesopathy of the        Achilles tendon) with signs of autoimmune disease        (undifferentiated collagenosis)    -   4. Irritable bowel syndrome with episodic diarrhoea    -   5. Secondary antibody deficiency syndrome (IgG and IgA)    -   6. Laboratory chemistry evidence of an autoimmune disease        (autoantibodies) relating to an undifferentiated collagenosis        History and Local Findings:

A long time ago (>10 years) the patient had herpes zoster (shingles) onthe forehead and upper jaw branch of the right trigeminal nerve, andonce the viral infection had cleared, chronic pain, numbness and episodeof acute pain persisted, especially behind the right eye, the nose andaround the right edge of the tongue (post-zoster neuralgia).

The facial pain attacks continued daily before or after an episode ofdiarrhoea, which was characterized by a rapid watery bowel movement(irritable bowel syndrome).

The facial pain attacks were also always accompanied by increasedperspiration and/or shivering.

Prior to the facial neuralgia, there had already been migraine withoutaura, which until the start of IgY therapy had occurred with an averageof 7 days each month.

At a later stage in the disease, the patient began to suffer from abilateral achillodynia, which gradually led to significant mobilityproblems. Achillodynia is a painful disease of the Achilles tendon,which occurs either as an independent inflammatory disease, e.g. afterstraining the tendon, or as a secondary symptom of a rheumatic disease.

Therapeutic Response of the Pain:

Long-term medication to control the pain consisted of a combination of 6different drugs: An antiepileptic (pregabalin), 2 antidepressants(amitriptyline and duloxetine), the analgesic flupirtine and the opioidstilidine and fentanyl (200 μg stick as required). The patient hadalready consulted 9 pain practices, neurology clinics and orthopaedists(for achillodynia). She suffered from all 3 pain syndromes withoutrelief, as well as irritable bowel syndrome and in addition the sideeffects of the many medications.

Evidence of a Significant Alleviation of the Disease Symptoms with OralTherapy with a Hyperimmunoglobulin Against Endotoxins (LPS) from EggYolk from Immunized Chickens (Anti-LPS Hyper-IgY):

Treatment with the specific IgY was started at the lowest trial dose(2×1.25 g). Once treatment had begun not a single further migraineoccurred. The achillodynia and the irritable bowel symptoms alsodisappeared within one month.

The post-zoster neuralgia was unchanged at this dose, as was medicamentuse. By doubling the dose (2×2.5 g) after 3 months of treatment at thelow trial dose, the facial pain attacks became much less frequent andthe duration of the attacks was shortened from one hour to just a fewminutes. The intensity of the pain remained unchanged. Some medicamentswere dispensed with completely, while others were reduced in dose. Thepatient's general well-being improved radically.

By substituting the (relatively minor) antibody deficiency withintravenous human immunoglobulins, all the remaining pain and diseasesymptoms disappeared completely, although numbness in the facial skinand tongue persisted.

Summary:

Post-Zoster Neuralgia

Post-zoster neuralgia is an independent clinical diagnosis of knownaetiology. This is a mononeuropathy consisting of permanent nerve damageafter a viral infection. Science has not come up with a satisfactoryexplanation as to why only some patients with shingles go on to developpost-herpetic neuralgia, which often remains untreatable for the rest ofa patient's life, after the infection has healed. The binding ofendotoxins to the nerve roots damaged by the infection could be one ofseveral mechanisms that are a partial cause of persistent pain. Thepresent case study strongly supports this hypothesis: While beingtreated with the specific IgY preparation, the patient's migraine,irritable bowel syndrome and inflammatory changes in the Achilles tendondisappeared. Such a significant impact can only be understood in termsof the neutralizing effect of IgY on the transport of endotoxins in theorganism. The significant reduction of the duration of facial painepisodes and their reduced frequency suggest that the same inductionmechanism at least is involved in this pain syndrome.

Achillodynia

The complete elimination of pain and inflammation in the Achilles tendonin the context of the autoimmune disease is surprising, particularlysince no treatment had previously afforded the patient any relief. It isknown that inflammatory enthesiopathies (an umbrella term for allinflammatory diseases of the tendon and tendon attachment) arefrequently resistant to treatment.

Migraine

The patient's migraine could not be treated adequately withmedicamentous seizure prophylaxis (β-blockers) and the specific migraineagents taken by the patient during an attack were not effective enoughto enable her to continue to work on days when she had migraines. Thisresulted in an average of 7 days of absence from work each month solelydue to the migraines. This example clearly shows that the transfer ofendotoxins has a unique and completely surprising part to play in thiscondition.

Example 5

Patient data: 65 years old, male, study number 17

Duration of the pain syndrome: Headaches for 35 years, neuropathy of theright sciatic nerve for one year, right epicondylitis for 3 years.

Diagnoses:

-   -   1. Persistent symmetrical tension-type headache since a severe        episode of “tick-borne encephalitis” (TBE) 1974 (Inflammation of        the brain and meninges caused by a virus carried by a tick bite)    -   2. Epicondylitis humeri radialis and ulnaris right with        substantial functional impairment of the entire right arm and        severe resting pain.    -   3. Lumbar back pain radiating across the entire right sciatic        nerve, the residual effect of surgical treatment for a herniated        disc a year ago (mononeuropathy of the sciatic nerve after        pressure injury).        Local Findings:

Very tender periosteum around the muscle attachments of the rightforearm muscles on the upper arm in the elbow area. Radiating painduring typical movements with tension on muscle attachments (turningscrews, writing, lifting objects with an outstretched arm, such as e.g.hanging coats on door hooks).

Throbbing pain in the lumbar spine, pain in the sciatic nerve whenpassively raising the right leg in a stretched position while lying down(positive Lasèque's sign), Achilles tendons and right patellar tendonreflex absent, no motor weakness in right leg.

Therapeutic Response of the Pain:

Having taken medication for the meningo-encephalitis for many years withsevere side effects (liver damage), the patient no longer takes anymedication for his pain. Physiotherapy as part of an in-patientrehabilitation programme (after the meningo-encephalitis and the discsurgery) had no lasting success

Evidence of a Significant Improvement in, and in Some Cases CompleteElimination of the Disease Symptoms with Oral Therapy with aHyperimmunoglobulin Against Endotoxins (LPS) from Egg Yolk fromImmunized Chickens (Anti-LPS Hyper-IgY):

During the study there was an improvement in all 3 pain phenotypes, thesignificant variations in pain level recorded before the study remained,the mean values began to decrease during the low-dose phase (2×1.25 gdaily), and this effect was even clearer at the higher dose (2×2.5 gdaily). In the follow-up observation phase, the back and sciatic paindisappeared completely while the patient remained on the higher dose.The pain and functional disturbances caused by the epicondylitis werereduced so much that the patient no longer experienced any functionalimpairment, because the pain was low even under physical stress. Duringthe follow-up phase the headache only occurred early in the morning andit was no longer of significance to the patient (see FIG. 6). In thegraphical representation of the numerical figures documented to rate thepain level in the pain diary, the patient had not entered daily averagevalues but rather the maximum values for each day, so that the patient'sassessment—relayed verbally—that he was largely pain free is notreflected.

In the laboratory part of the study, the patient showed a comparativelysmall reduction in endotoxin-activated monocytes in the peripheral blood(reduction through apoptosis), a slight decrease in the total number ofmonocytes to normal values, and quantitative analysis of 22immuno-messengers (chemokines, cytokines, growth factors) showed, incomparison to other study participants, a disproportionate reduction inthe plasma concentrations of inflammatory proteins (e.g. TNFα, IL-6,IL-8), with the highest values for the increase in anti-inflammatoryprotein factors (e.g. interleukin 4 and 5).

Withdrawal Attempts:

The patient finished taking IgY after 141 days for a period of 6 monthsuntil the headaches and pain of the epicondylitis began to affectquality of life again. Thereafter he took the medication only as neededfor periods of 4-5 days, and was then able to control the pain level asdesired.

Summary:

Chronic Headache after Meningitis, Mononeuropathy of the Sciatic Nerveafter Nerve Root Compression, Epicondylitis

The monocyte-bound “endotoxin load” in the patient's blood seems to beimplicated in the aetiology of 3 chronic pain phenotypes that arenormally diagnosed independently in medicine. The residual damage to thebrain and meninges (TBE) following the viral infection, and to thesciatic nerve following root compression are the biological weak pointswhere endotoxin-laden immune cells can become attached and maintain alocal immune reaction (cause of pain). The causal explanation for thisepicondylitis is an immune activation in the neural supply of the rightarm (and not the painful elbow).

FIG. 6 illustrates the changes in intensity of 3 different classifiedpain symptoms (epicondylitis, headache and back-sciaticpain/mononeuropathy) of this patient based on self-assessment of NRSscores over the study period and during subsequent follow-up, when thepatient continued to take IgY at a low maintenance dose until day 141.

The measurement points on the ordinate correspond to NRS values thatwere taken from the diary (there was no 3-day average due to relativelylow fluctuations in the pain level). The abscissa gives the time indays. IgY treatment began on day 15 and continued in double the dosefrom day 29 to day 42. Thereafter the treatment was continued at a lowmaintenance dose until day 141.

Example 6

Patient data: 65 years, male

Duration of the pain syndrome: 11 years with interruption of symptomsfor 3.5 years after an operation (the Jannetta procedure).

Diagnoses:

-   -   1. Trigeminal neuralgia, II. and III. right branch (diabetic        mononeuropathy)    -   2. Type I diabetes stabilized with insulin pump, diabetic distal        leg polyneuropathy, diabetic nephropathy (proteinuria, still        normal function)        History and Local Findings:

The neuralgia began more than 10 years after onset of diabetes,initially responding to carbamazepine, then additionally otheranticonvulsants, and finally microvascular decompression of thetrigeminal root (MVD or synonymously: the Jannetta procedure). 3.5 yearspain-free. When the attacks began again, the dose of carbamazepine wasincreased rapidly, leading to pronounced side effects affecting thecentral nervous system, with the threat of disability (threatened lossof driving licence, professional driver).

Finding:

Tingling malaise in a small area of the upper lip and the oral mucosa ofthe cheek in the lower jaw. Strongly avoids creating air currents orcontact that might trigger pain attacks in these areas. Repeated dailybursts of pain in quick succession brought on by eating, but still justtolerable with toxic blood levels of the antiepileptic drug (apparentlylow level of pain at the start of the study in FIG. 7). Work-relatedstress and personal issues increased the likelihood of an attack.

The distal leg polyneuropathy is purely sensory and consists of thesensation of walking on cotton wool, and oedemas in the feet and lowerlegs.

Evidence of Complete Remission (Elimination) of the Trigeminal Neuralgiaand Improvement of Symptoms of the Diabetic Polyneuropathy withTreatment with the Hyperimmunoglobulin Against Endotoxins (LPS) from theEgg Yolk of Immunized Chickens (Anti-LPS Hyper-IgY):

Within the first 14 days of study, at an IgY-dose of 2×1.25 g per day,the patient was already pain-free, and the patient reduced thecarbamazepine dose from 1,200 mg to 900 mg with the effect that, whilehe no longer suffered from the side effects, the attacks began to recur.On a doubled dose of IgY of 2×1.25 g daily, the patient was againpain-free, and carbamazepine was reduced to a daily dose of 450 mg forthe remainder of the study (see FIG. 7). The sensory symptoms in skinand mucosal areas, which were the main sites of the pain attacks,disappeared completely during IgY therapy. For idiopathic trigeminalneuralgia there are no sensory disturbances, with the exception oftherapeutic interventions that cause damage to the nerves. This case wastherefore a diabetic mononeuropathy in the area of the trigeminal nerve,and not an idiopathic form of neuralgia.

While on IgY therapy, the patient also recovered the sensation in bothfeet, and the tendency towards oedema in the feet and lower legs wassignificantly lower. In these regions of diabetic polyneuropathy, thepatient had no pain. The effect on symptoms of polyneuropathy issurprising.

Thereafter, the patient, while taking a daily dose of IgY of 5 g, wasable after one month to stop taking the antiepileptic drug carbamazepinecompletely and remained symptom-free on an IgY maintenance dose of 2.5 gof IgY per day. On repeated attempts to lower this daily dose, thesensory disturbances returned in the same places that the patienttypically knew as heralding pain attacks.

In the laboratory part of the study the patient showed a significantreduction of endotoxin-activated monocytes in the peripheral blood(reduction through apoptosis), and a significant decrease in the totalnumber of monocytes. Quantitative analysis of 22 immuno-messengers(plasma concentrations of chemokines, cytokines, growth factors) showeda significant reduction in growth factors IGF-1 and GMCSF andproinflammatory cytokines IL-8 and IL-7, and an increase inanti-inflammatory cytokines IL-4, IL-5 and IL-13 in the patient.

Withdrawal Attempts:

The patient could only reduce the dose of study medication (5 g dailydose of IgY), a period without treatment was not possible. Thespecificity of the effect of the dominant set of antibodies againstendotoxins was compared with a therapy involving a hyperimmune IgYpreparation against antigens of periodontosis pathogens.

Summary:

Diabetic Mononeuropathy of the Trigeminal Nerve

The sustained elimination of the symptoms of idiopathic trigeminalneuralgia through long-term treatment with oral immunoglobulins frombovine colostrum is already known, but not for trigeminal neuralgia onthe basis of diabetic mononeuropathy, as in this example.

Diabetic Polyneuropathy

In this example, the concomitant therapeutic influence on the sensoryand autonomic components of polyneuropathy (loss of sensation and lowerleg oedemas) gave the first surprising indication of the effectivenessof the preparation in diabetic polyneuropathy.

FIG. 7 illustrates changes in the intensity of pain attacks resultingfrom trigeminal neuralgia by means of patient self-assessment using NRSscores for the study period. The ordinate shows the self-assessment ofthe pain level by the NRS for each day. The study days are shown on theabscissa. Treatment began on day 15 and continued at double the dosefrom day 29. Before IgY therapy, pain had been poorly controlled withcarbamazepine in a daily dose of 1,200 mg, which had already resulted intoxic levels of the drug in the blood. On starting IgY therapy (from day15), the carbamazepine dose was reduced at intervals until the end ofthe study, down to a daily dose of 450 mg (day 42). At the end of thestudy the patient was symptom-free. Carbamazepine was completelydiscontinued thereafter.

Example 7

Patient data: 43 years old, female

Duration of the illness: 9 years

Diagnoses:

-   -   1. Complex regional pain syndrome of lower right extremity    -   2. Idiopathic back pain    -   3. Exceptionally severe irritable bowel syndrome, complicated by        daily uncontrolled bowel evacuation during stomach cramps    -   4. Painful bladder syndrome/interstitial cystitis (PB/IC), also        with bladder cramps and uncontrolled urination        History and Local Findings:

After hallux valgus surgery on the right foot, 5 further attempts at acure by surgery were carried out as a result of lingering postoperativeextremely severe neuropathic pain presenting as a complex regional painsyndrome that would not respond to medicaments

The pain improved with multimodal pain therapy with limited strength inthe foot.

Following unsuccessful attempts to treat the inflammation and extremepain with medicaments, (long-term antibiosis owing to suspected chronicinfection, anti-inflammatory long-term medication), the existingirritable bowel symptoms became completely uncontrollable. Theintestinal colic was associated with watery stools, which were mainlypassed in bed at night in an uncontrolled manner. The painful bladderspasms led to loss of control of the sphincter muscle.

Evidence of a Significant Remission (Elimination) of Bowel and BladderDisease Symptoms with Treatment with the Hyperimmunoglobulin AgainstEndotoxins (LPS) from Egg Yolk from Immunized Chickens (Anti-LPSHyper-IgY):

The neuropathic pain symptoms in the right foot had already improvedunder previous multimodal therapy (combined partial in-patienttreatment, involving psychological, physio- and drug therapy), and onlyimproved slightly during treatment with the study preparation. The footcould still no longer bear any load. Back pain, particularly severe inthe neck and shoulder area and the lumbar-sacral region, improvedlastingly by 2 points on the numerical rating scale. The bowel andbladder spasms disappeared completely towards the end of the IgY studyon a daily dose of 5 g of the specific IgY preparation. The number ofdaily bowel evacuations fell from an average of 9 (2-17) to 2 (see FIG.8), the stool no longer contained any undigested food constituents, andwas formed. Uncontrolled bowel movements and urination ceasedcompletely.

Thereafter, the results of the treatment were maintained over a yearwith a daily dose of IgY of 4 g.

In the laboratory part of the study the patient showed typical responsesto treatment, in particular a significant reduction ofendotoxin-activated monocytes in the peripheral blood (reduction throughapoptosis) and a significant decrease in the total number of monocytes.In the quantitative analysis of 22 immuno-messengers (plasmaconcentrations of chemokines, cytokines, growth factors), a significantreduction in growth factors IGF-1 and GMCSF and proinflammatorycytokines IFN-γ, TNFαR-1, IL-8 and IL-6, and an increase inanti-inflammatory cytokines IL-4, IL-5 and IL-13 are to be singled out.

Withdrawal Attempts:

Several attempts were made to end IgY-therapy, but each time the boweland bladder symptoms returned after a few days.

Summary:

Irritable Bowel Syndrome, Painful Bladder Syndrome/Interstitial Cystitis(PBS/IC), Also Symptoms of an Autonomic Neuropathy

Irritable bowel syndrome of this severity is certainly a rarity, as isthe combination with comparable bladder symptoms. 9 years of failedattempts to treat the foot and the extreme pain with medicamentoustherapy has resulted in considerable damage to the barrier function ofintestinal mucosa and certainly promoted and contributed to the unusualextent of the disease. The over 90% endotoxin-activated blood monocytes(CD14+ and CD45+) before the IgY treatment ultimately reveal theconsequences of this barrier damage, which with the insufficientapoptosis of antigen-receiving monocytes in the intestine has led to anabnormally high endotoxin load in the whole organism. In laboratorytests at the end of study, monocytes with endotoxin binding (CD14+) hadfallen to 65% and the “activated” monocytes (CD45+) had fallen to 10%.The simultaneity of the bowel and bladder symptoms with significantdysfunctions of the sphincter muscles of both organs suggests thatendotoxins were the primary cause of an autonomic neuropathy. Bowel andbladder pain and dysfunctions could therefore largely be interpreted asdamage to the autonomic nerve supply of both organ systems under theinfluence of endotoxins.

FIG. 8 shows the action/effect of the IgY preparation on 3 quality oflife parameters (sleep quality, activity and bowel movement) in thispatient, who had an extreme manifestation of irritable bowel syndromewith diarrhoea.

The ordinate shows the self-assessment score for “sleep quality” and“activity” using NRS daily values and the daily number of bowelmovements.

The abscissa shows the time in days. The study medication was started inday 15, and continued in double the dose from day 29 to day 42.

Example 8

Patient data: 55 years, male

Duration of the illness: 19 years

Diagnoses:

-   -   1. Post-Lyme borreliosis syndrome with signs of chronic        encephalitis, condition after Lyme carditis    -   2. Polyneuropathy    -   3. Irritable bowel syndrome with diarrhoea    -   4. Chronic exhaustion/fatigue syndrome (CFS)    -   5. Polymorphic photodermatosis        History and Local Findings:

Erythema chronicum migrans, subsequently Borrelian radiculitis(Garin-Bujadoux-Bannwarth syndrome), encephalitis, and polyneuropathy.Oral and intravenous long-term antibiosis resulting in severe intestinalsymptoms caused by bacterial overgrowth. Full disability because of thepain and the extreme form of CFS.

Thereafter: Onset of polymorphic photodermatosis

Intermittent treatment of nerve pain (polyneuropathy) with polyvalenthuman immunoglobulins (IVIg). This therapy gave substantial control ofthe pain and CFS and resulted in a marked improvement in thephotodermatosis. Further improvement in the photodermatosis aftereradication of chronic Helicobacter pylori infection of the stomach(duration of the improvement: 6 months).

Thereafter the IVIg no longer had a curative effect. The patient livedin a completely darkened room, with only UV-B-free artificial light.Largely bedridden, home care.

Evidence of a Significant Improvement in the Polyneuropathy,Photodermatosis, CFS and Irritable Bowel Syndrome with Treatment withthe Hyperimmunoglobulin Against Endotoxins (LPS) from Egg Yolk ofImmunized Chickens (Anti-LPS Hyper-IgY):

Admitted to in-patient care at the Dermatological University ClinicWürzburg.

Admitted to a completely daylight-proof single room. Continued paintherapy (polyneuropathy) with gabapentin, starting treatment with thespecific IgY preparation in a daily dose of 2×1.25 g. This resulted in asignificant improvement in neuropathic pain and complete normalizationof bowel movement. After one week, the IgY preparation dose wasincreased to 3×1.5 g daily. On this treatment, there was a dailyincrease in exposure to daylight from 300 to 9,000 lux per day untildischarge for home care after 4 weeks.

Summary:

Polyneuropathy after Neuroborreliosis, Chronic Exhaustion/FatigueSyndrome (CFS), Irritable Bowel Syndrome, Polymorphic Photodermatosis

All the disease symptoms were controlled by IVIg over a 6-year period,to the extent that although the patient remained unable to work, he waslargely self-sufficient. Even under optimum conditions, i.e. in thefirst 4 weeks after each intermittent treatment of 30 g of IVIg, thepatient could not walk more than 500 m 3 times per day. The exerciselimits were determined by increased pain, exhaustion symptoms, andextremely itchy inflammatory skin changes when the low light tolerancethreshold was exceeded. Skin changes, once they appeared, took weeks toheal. The antiepileptic gabapentin provided minimal relief within narrowlimits at least for the itching. Antihistamines and cortisone brought norelief.

Polyneuropathy

The polyneuropathy was characterized by shooting pains when moving,which were projected into regions of the body with reduced sensitivity,mainly in the left hemisphere of the body. In addition, there wassymmetrical pain in the 2nd and 3 trigeminal branches caused by chewingor touching of the skin (trigeminal neuropathy). During treatment withIgY, symptoms of trigeminal neuropathy disappeared completely, and otherpain was reduced so much that, despite the very weak condition of thepatient, activities such as getting out of bed, dressing, showering,writing and walking short distances were possible without any pain.

CFS

The severe daytime fatigue, which throughout the disease was onlyperiodically interrupted when the patient was being treated with IVIg,was alleviated under therapy with IgY to the extent that the patient wasable to participate in most day-to-day activities without needing abreak.

Irritable Bowel Syndrome

Irritable bowel syndrome consisted of abdominal spasms and frequentevacuation of unformed stools. Notably, the patient reported that he wasnever able to fully empty the rectum, and that for half-hour or longerafter bowel movements small semi-liquid quantities were still passedunnoticed, so he was forced to wear pads. This loss of control overbowel evacuation was a clinical sign of autonomic neuropathy. Thesesymptoms already disappeared in the first week of treatment with IgY.

Polymorphic Photodermatosis

The polymorphic photodermatosis was extremely acute. Testing a smallarea of skin with a defined dose of UV-B already produced a vigorouslocalized reaction with the typical dermatological results of thedisease.

The response of this particularly severe clinical condition to IVIg isdescribed in case reports, as are successful treatments byplasmapheresis (plasma exchange treatment).

The significant partial success of treatment with anti-endotoxinhyperimmune IgY on the one hand is very surprising, and on the otherprovides evidence of the involvement of endotoxins in the aetiology ofthis individual example.

Example 9

Patient data: 59 years, male

Duration of the illness: 6 months

Diagnoses:

-   -   1. Carcinoma of the floor of the mouth (right side), operated,        irradiated    -   2. Diabetes mellitus type I    -   3. Neutropenia, anemia (as a result of radiotherapy)    -   4. Neuropathic facial pains    -   5. Mucositis of the irradiated oral mucosa        History and Local Findings:

Since radiotherapy of the operated area in the region of the right lowerjaw/floor of the mouth, the patient had experienced acute bouts offacial pain radiating from the lower jaw into the right ear, brought onby swallowing. Severe burning sensation in the oral mucosa in theirradiated area.

Resting pain largely controlled with tramadol+metamizole. Almostimpossible to eat because of pain.

Initially treatment with 6.4 g of subcutaneous immunoglobulin. Afterjust a few hours the neuropathic facial pain was alleviated, but not thelocal contact pain of the oral mucositis.

Evidence of a Significant Improvement in the Mucositis, Unhindered OralIntake of Food while being Treated with the Hyperimmunoglobulin AgainstEndotoxins (LPS) from Egg Yolk of Immunized Chickens (Anti-LPSHyper-IgY):

Immediate response of contact pain in the inflamed oral mucosa ondrinking and eating. Normal food intake largely restored.

Summary:

The bacterial colonization of the oral mucosa may containendotoxin-producing germ populations. The sensory nerve endings of thetrigeminal nerve carry binding sites for endotoxins (Toll-like receptor4), so that endotoxins can cause extreme pain hypersensitivity ininflamed mucosal lesions. The binding of the endotoxin by locallyadministered antibodies eliminates not only the pain but also theinflammation caused by endotoxins. Unlike local anaesthetic measures,the antibodies also accelerate healing.

The abovementioned examples were all carried out with the antibodypreparation from Preparation Example 1. The therapeutic successes forthe uses according to the invention are not limited exclusivelyprecisely to this Preparation Example 1. Preparation Example 2 wasemployed in the following examples. It is moreover probable that evenbetter results can be achieved with alternative preparations than withthe Preparation Examples 1 and 2 employed. It is of course possible herefor the person skilled in the art to optimize the preparationcomposition in the context of the agent to be used or the preparationfor individual indications or even where appropriate for individualpatients. It is accordingly of course clear to the person skilled in theart that the use according to the invention relates not only toPreparation Examples 1 and 2 employed in the examples, but thesurprising effects are also to be expected with other agents orpreparations to be used according to the invention.

Example 10

Patient data: 13 years old, male

Duration of the disease 6 months

Diagnoses:

-   -   1. Acute right periarthritis humero-scapularis (rotator cuff        tendinitis)        History and Local Findings:

For about 1 week the patient has been suffering from increasing movementpain in the right shoulder joint. After 5 days an additional nocturnalrest pain occurred and after 6 days complete inability to use the rightarm. Bending in the elbow joint is so painful that independent dressingand closing of the first are impossible (shoulder pain triggered).

The youth cannot remember a triggering trauma or excessive strain. Thehistory shows only an allergic asthma, which did not exist, however, atthe start of the pain symptoms.

The right shoulder joint is extremely painful to pressure in the regionof the entire rotator cuff. Compared with the opposite side, an increasein temperature is also to be found here. A slight diffuse swelling ofthe soft tissue around the shoulder joint into the region of the uppershoulder blade is moreover to be observed. Any active movement of thearm and hand is avoided by the patient. The passive mobility of theshoulder joint is limited maximally because of pain being triggered inall movement axes.

These were typical symptoms of an idiopathic acute periarthritis whichwas hitherto untreated.

Evidence of a Complete Cure of the Periarthritis Under Treatment withthe Hyperimmunoglobulin Against Endotoxins (LPS) from Egg Yolk ofImmunized Chickens (Anti-LPS Hyper-IgY):

Therapy was conducted by administration of 2×½ sachets of IgYeffervescent powder (daily dose; corresponds to 2×2.5 g of antibodymixture). No analgesics were prescribed or taken.

First follow-up consultation on the morning after the start of therapy:

The patient had slept through the night again, could already dresshimself independently in the morning and also tie his shoes. Greetingwith a cautious handshake was possible, as well as spontaneous bendingof the elbow joint, without considerable pain being triggered in theshoulder.

Within 5 days a continuous improvement to absence of symptoms occurred.A total of 7 sachets of the IgY preparation were taken. The lastconsultation with the patient took place after a further 6 weeks. Norecurrence of the symptoms occurred.

Summary:

This was an acute idiopathic periarthritis of a shoulder joint withoutprior treatment. The IgY therapy led to a rapid cure without trace,which already started with the first dose and was complete after 5 days.

Example 11

Patient data: 51 years old, male

Duration of the illness 7 years

Diagnoses:

-   -   1. Pemphigus vulgaris        History and Local Findings:

The disease has existed for 7 years. It is a rare autoimmune disease ofthe skin and mucous membranes. The manifestation in the region of theoral mucous membrane causes losses of the mucous membrane over largeareas, which leaves behind extremely painful ulcers (in the sense ofmucositis) which heal only under chemotherapy of the disease.

During this period oral intake of food and liquid is scarcely possible.

It has so far been possible to interrupt the disease in ever longerphases by chemotherapy. However, all attempts to gradually reduce thechemotherapy resulted in recurrences, which usually started in theregion of the oral mucous membrane.

Since treatment of the oral mucous membrane with IgY it has beenpossible to maintain oral nutrition in the last two bouts of thedisease, since the pain already started to largely subside a few hoursafter the start of intake.

In the last few days the patient has found small areas of painful mucousmembrane defects in the mouth again, a sure sign of a renewed recurrenceof the disease.

Individual Healing Attempt with IgY:

A local symptomatic therapy with IgY effervescent powder in a dose of2×1.25 g per day (IgY preparation from Preparation Example 2) was firstcarried out until food intake was possible again unimpeded and withoutpain (maximum of one week).

Thereafter treatment with the enteric presentation form of the IgYpreparation was started with the intention of eliminating LPS aspossible triggers of the systemic disease already in the region of thesmall intestine.

Dosage: 3×3 enteric tablets daily for the duration of one month(corresponds to almost 3.4 g daily of IgY preparation from PreparationExample 2).

During this time the oral treatment with IgY effervescent powder wascontinued in a minimal dosage to maintain the intact oral and pharyngealmucous membrane.

The materials required in the 1st month: daily 3×3 enteric tablets(almost 3.4 g daily dose of the IgY preparation from Preparation Example2). 270 enteric tablets and 37 daily dose units of effervescent powderare made available.

The decision to continue the treatment in the same or a changed dosetakes place at the end of each monthly period. The therapeutic effect ischecked by diary entries of the symptoms of the disease, course and doseof the immunosuppressive chemotherapy.

This is the first attempt at therapy of a patient suffering frompemphigus vulgaris with IgY. Treatment of the mucositis (oral mucousmembrane) of this patient was successful on every application in thepast.

Further Course of the Disease Under Treatment with IgY (Status: Oct. 3,2012):

After the painful mucosal lesions of the oral/pharyngeal cavity hadsubsided under administration of IgY effervescent powder, a considerableimprovement in general well-being already occurred 4 days after thestart of taking the enteric tablets (3×3 tablets daily).

-   -   Complete elimination of the chronic exhaustion symptoms    -   Re-established physical capacity    -   Elimination of non-specific joint pain in the region of the        shoulder girdle

At the next analysis of the specific antibody titre (autoantibodies) inthe University Dermatology Clinic, the lowest titre since the start ofthe disease (1:300) was measured. Before the treatment this titre was>1:10,000.

After taking blood to determine the immunological activity parametersunder the optimum clinical state, the IgY therapy was ended after 6months.

After a therapy pause of almost 4 months, symptoms of the pemphigusvulgaris arose again for the first time at the end of February 2012(oral mucosal lesions and blisters on areas of skin in the region of theupper part of the body). Non-specific joint pain and mild exhaustionsymptoms preceded the recurrence of the autoimmune disease.

Blood was taken again for analysis of the autoantibodies and theimmunological activity parameters. The titre of specific autoantibodieshad risen only slightly (1:400).

Treatment with IgY was resumed again. 1 sachet of effervescent powderper day and 3×3 enteric tablets were administered (corresponds to adaily dose of almost 8.4 g of the IgY preparation from PreparationExample 2).

The non-specific pain symptoms disappeared within a few days and the(slightly pronounced) erosions of the oral mucous membrane healedrapidly. No new blisters occurred on the skin and the old ones healedwithin 14 days.

In this Course a Healing Effect of the IgY Preparation on the EntireSymptoms of the Autoimmune Disease is Now without Doubt to beRecognized.

The recurrence of the disease after a 4-month pause in the therapy couldbe suppressed for the first time without using dexamethasone andmycophenolate mofetil.

Example 12

Patient data: 41 years old, female

Duration of the disease 9 months (after bone marrow transplant (BMT)because of leukaemia)

Diagnoses:

-   -   1. Chronic graft-versus-host disease (GvHD).        History and Local Findings:

9 months after the BMT a chronic GvH developed in the oral and genitalmucous membranes and a GvH keratoconjunctivitis. Short time later: acuteinvolvement of the lungs in the GvH with global insufficiency of thelungs requiring ventilation. After surviving the lung GvH a long-termtherapy was carried out with prednisolone in a daily dose of between 20and 30 mg, in addition to the chemotherapy of the leukaemia. Thecortisone administered leads to a pronounced Cushing's disease syndrome.

The chronic GvH of the mouth and eyes and of the vaginal mucousmembranes allows no reduction in the cortisone dose below 20 mg. Thelung is currently not affected, but still subject to significantrestrictions in function.

From March/April 2011 oral IgY therapy was started with a daily dose of2 teaspoons of powder (corresponds to approx. 2.5 g of IgY preparationfrom Preparation Example 2) in a vanilla yoghurt. An improvement in themouth and eye involvement was to be observed, but not in the genital GvHsymptoms. The amount of prednisolone administered could be reduced to adaily dose (DD) of 15 mg.

A “wash out” phase followed for the duration of one month.

Individual Treatment Plan of the Therapeutic Attempt with Enteric IgYTablets and (Optionally) IgY Effervescent Powder.

The treatment plan provides for initially administration of 3×3 enterictablets daily (daily dose of almost 3.4 g) for the duration of 4 weeksin the 1st month. 270 enteric tablets of IgY are provided in the 1stmonth.

All the symptoms of the GvH are recorded. Under consultation with thetreating oncologist and depending on the clinical findings, the dose ofcorticoid administered and therefore the accompanying immunosuppressionare to be reduced. In the event of clinical remission of the GvHsymptoms, the therapy is continued in the same dosage until thecortisone therapy has been gradually phased out completely. If remissionof the symptoms is not complete or it is necessary to maintain thecortisone medication, additional taking of effervescent powder isenvisaged in the next step for the duration of a further 4 weeks. 270enteric tablets of IgY are provided in the 2nd month.

The treatment plan furthermore provides for an identical dose of enterictablets (3×3 tablets; almost 3.4 g daily of Preparation Example 2) forthe duration of a further 4 weeks in the 2nd month to be administered,and the additional dose of 2×½ sachets of effervescent powder (5 g ofIgY preparation from Preparation Example 2) (in each case based on thedaily dose. The question of whether the oral action brings an additionalbenefit for the oral and possibly also the conjunctival manifestation isto be investigated. 270 enteric tablets and additionally 30 sachets of“effervescent powder” of IgY are provided for the 2nd (and whereappropriate 3rd) month.

If an overall optimum action does not occur, the dose of the enteric IgYtablets is to be increased to 3×4 tablets (daily dose of 4.5 g of IgYpreparation from Preparation Example 2) for the duration of a further 4weeks and additional effervescent powder is to be administered only inthe event of prior benefit. 360 enteric tablets and additionally afurther 30 sachets of “effervescent powder” of IgY are provided for the4th month.

If a complete remission of the GvH without cortisone medication resultsfor any period of at least 1 month, the dose is to be reduced down tothe maintenance dose by 3×1 tablet (daily dose) in weekly steps. Themaintenance dose is then still to be determined.

The corner times of blood samples (if necessary also stool samples) are:

-   -   1. At the end of the “wash out” phase and before the start of        the first 4-week period, while the enteric IgY tablets are being        administered    -   2. After the first 4-week period    -   3. After discontinuation of cortisone    -   If a remission occurs    -   If clinical symptoms return when the dose is reduced.

In the event of a positive action, the patient can continue to receivethe preparation in a dose according to requirements. In the event ofcomplete remission of the symptoms over a period of 2 months, awithdrawal is attempted.

The GvH symptoms have been recorded by the patient in a diary since thebeginning of March 2011 by a visual analogue scale (pain) and thevisible symptoms documented by the specialist.

This was the first attempt at therapy of a chronic GvH with IgY.

Results of this Individual Healing Attempt:

Because of an unforeseen increase in the tumour markers in April 2011and the associated need for a rapid exit from the cortisone medication,the first blood sample was already taken 4 weeks after the end of thetest phase with IgY effervescent powder. The cortisone medication hadalready been discontinued at this point in time and the IgY therapy wasthen started, in contrast to the original treatment strategy,immediately with 3×4 tablets of the enteric formulation combined withone sachet of effervescent powder.

The acute increase in the tumour markers was a typical consequence ofthe high-dosed cortisone medication which was necessary to suppress theGvHD. Cortisone inhibits not only the graft-versus-host reaction (GvHR),but to the same extent also the antitumour activity of the donated bonemarrow (inhibition of the graft-versus-tumour activity).

Under this therapy there was a constant improvement in all the diseasesymptoms of GvHD (in spite of discontinuation of cortisone). The tumourmarkers could soon no longer be detected in the blood. The chemotherapywas therefore decreased stepwise to a minimal dosage. In August 2011 thepatient resumed her employment after 1½ years, and in January 2012 inthe state of an almost complete re-establishment of capacities blood wastaken a second time for analysis of the immunological activityparameters.

The IgY therapy is being continued in the combination of theeffervescent powder with the enteric tablets in a slow reduction of thedose. If the positive state continues to remain stable, complete exitfrom oncological drug therapy is planned.

Example 13

Patient data: 55 years old, male

Duration of the illness 18 months

Diagnoses:

-   -   1. Bilateral chronic epicondylitis (more acute on the right        side)        History and Local Findings:

The patient is a sports teacher, swimming team trainer and sportstherapist in a physiotherapy practice. The epicondylitis has existed for18 months, initially only on the right, in the further course of thedisease on both sides more acute on the right, always limited to theradial epicondylus.

Treatments to date have taken place in an orthopaedic practice.Antiinflammatory oral drugs provided no relief. Local injections withlocal anaesthetics and cortisone led to alleviations, which for sometime have lasted a maximum of one day. Physiotherapy, tapes and otheraids were not able to influence the progress of the symptoms.

Individual Healing Attempt with IgY:

The individual healing attempt with IgY was started when nocturnalresting pain no longer allowed cohesive night-time sleep and morningweakness in closing a first (both sides) for a duration of about 1 hourno longer guaranteed the patient was fit for work.

There were no further disease symptoms and this was the first painsyndrome at all for the patient.

The IgY therapy was started with the effervescent powder preparationwith a daily dose of 1 sachet (5 g of IgY preparation from Preparationexample 2).

In the course of the first treatment week no alleviation of the symptomsoccurred.

Only in the 2nd week was there a significant reduction in pain to abouthalf the starting level, and only rarely waking up in the night due toresting pain.

This improvement lasted for about 3 weeks, until the pain increasedagain after an infection of the upper respiratory passages (bronchitis,maxillary sinusitis). Thereafter, an additional IgY therapy with enterictablets (in a dose of 2×4 tablets; corresponds to 3 g of IgY preparationfrom Preparation Example 2) was started.

Under this combination a virtually complete elimination of the symptomsthen occurred for the first time. The patient reported waking up in themorning without stiff fingers, full capacity of the radial lower armmuscles and absence of nocturnal pain.

Residual symptoms no longer existed daily, the residual symptomsessentially being a sensitivity of the elbow to impact. Performancesport (cross-country skiing) is possible without restriction if thetherapy is continued.

Two blood samples were taken to analyse the immunological activityparameters, one before the start of treatment and one in the state ofsubstantial absence of symptoms.

The invention claimed is:
 1. A method for treating oral mucositis afterradiotherapy and/or chemotherapy comprising the step of administeringorally to a subject in need thereof, a pharmaceutical preparationcomprising an efficacious amount of IgY antibodies or their fragments,wherein said IgY antibodies or their fragments areanti-lipopolysaccharide polyclonal antibodies obtained from egg yolk ofhens immunized with Gram-negative bacteria.
 2. The method according toclaim 1, wherein the preparation comprises anti-lipopolysaccharide IgYantibodies obtained from egg yolk of immunized chickens.
 3. The methodaccording to claim 1, wherein the treatment is carried out byadministering a daily dose of a formulation prepared for administrationof 0.1-10.0 g.
 4. The method according to claim 1, wherein the treatmentis carried out by administering a daily dose of a formulation preparedfor administration of 1.0-8.0 g.
 5. The method according to claim 1,wherein the treatment is carried out by administering a daily dose of aformulation prepared for administration of 2.0-7.0 g.
 6. The methodaccording to claim 1, wherein the treatment is carried out by a dailyadministration for 4-14 weeks.
 7. The method according to claim 1,characterized in that the oral mucositis after radiotherapy and/orchemotherapy is present in a patient further suffering from anidiopathic pain syndrome.
 8. The method according to claim 1, whereinthe oral mucositis after radiotherapy and/or chemotherapy is present ina patient with a defective biological barrier against bacterialendotoxin.
 9. The method according to claim 1, wherein said IgYantibodies or their fragments represent at least 1.5 wt % based on thetotal weight of the preparation.
 10. The method according to claim 1,wherein said IgY antibodies or their fragments represent at least 2.0 wt% based on the total weight of the preparation.
 11. The method accordingto claim 1, wherein said IgY antibodies or their fragments represent atleast 5.0 wt % based on the total weight of the preparation.
 12. Themethod according to claim 1, wherein said IgY antibodies or theirfragments represent 100% of the total antibody content of thepreparation.